1. Summary of the Invention
The present invention is related to antibodies directed to the antigen PDGFD and uses of such antibodies. In particular, in accordance with the present invention, there are provided fully human monoclonal antibodies directed to the antigen PDGFD. Nucelotide sequences encoding, and amino acid sequences comprising, heavy and light chain immunoglobulin molecules, particularly sequences corresponding to contiguous heavy and light chain sequences spanning the framework regions and/or complementarity determining regions (CDR's), specifically from FR1 through FR4 or CDR1 through CDR3, are provided. Hybridomas or other cell lines expressing such immunoglobulin molecules and monoclonal antibodies are also provided.
2. Background of the Technology
Polypeptide growth factors exerting effects in a variety of tissues have been described. Such growth factors include platelet-derived growth factor (PDGF).
The platelet derived growth factor (PDGF) family currently consists of at least 3 distinct genes, PDGF A, PDGF B, and PDGF C whose gene products selectively signal through two PDGFRs to regulate diverse cellular functions. PDGF A, PDGF B, and PDGF C dimerize in solution to form homodimers, as well as the heterodimer.
Expression of RNA encoding the PDGF A and PDGF B subunits of has been reported in vascular tissues involved in atherosclerosis. PDGF A and PDGF B mRNA have been reported to be present in mesenchymal-appearing intimal cells and endothelial cells, respectively, of atherosclerotic plaques. In addition, PDGF receptor mRNA has also been localized predominantly in plaque intimal cells.
The PDGF B is related to the transforming gene (v-sis) of simian sarcoma virus. The PDGF B has also been reported to be mitogen for cells of mesenchymal origin. The PDGF B has in addition been implicated in autocrine growth stimulation in the pathologic proliferation of endothelial cells characteristically found in glioblastomas. PDGF has also been reported to promote cellular proliferation and inhibits apoptosis.
A novel PDGF, PDGF-D, has recently been cloned and characterized. See LaRochelle et al. Nature Cell Biology 3:517 (2001), GenBank Accession No. AF335584, International Patent Application No. WO 01/25433, U.S. Ser. No. 60/158,083, filed Oct. 7, 1999; U.S. Ser. No. 60/159,231, filed Oct. 13, 1999; U.S. Ser. No. 60/174,485 filed Jan. 4, 2000; U.S. Ser. No. 60/186,707 filed Mar. 3, 2000; U.S. Ser. No. 60/188,250, filed Mar. 10, 2000; U.S. Ser. No. 60/223,879, filed Aug. 8, 2000; U.S. Ser. No. 60/234,082, filed on Sep. 20, 2000; U.S. Ser. No. 09/685,330, filed on Oct. 5, 2000; PCT Application US00/27671, filed Oct. 6, 2000; U.S. Ser. No. 09/688,312, filed Oct. 13, 2000 and U.S. Ser. No. 09/715,332, filed Nov. 16, 2000. Each of these applications is incorporated by reference in its entirety., the disclosures of which are hereby incorporated by reference. Because of its expression profile and sequence homology and/or similarity to the above-discussed genes and gene products, antibodies to the PDGF-D antigen could be useful therapeutically.